Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease in the United States. It encompasses both a fatty liver and nonalcoholic steatohepatitis (NASH). The NASH Clinical Research Network (NASH CRN) was established in 2002 to conduct research related to the clinical features, risk factors, pathogenesis, natural history and treatment of NAFLD in children and adults. Encouraged by its success, the NIDDK has issued RFA-DK-08-505 whose objective is to continue the NASH CRN for five more years. The objectives of the NASH CRN during the next five years are: (1) to successfully complete three network wide studies initiated during the initial funding period. These include an observational longitudinal study of NAFLD in adults and children (NAFLD database study, n=1215), a randomized double blind controlled trial of pioglitazone or vitamin E vs. placebo (PIVENS) (n=247) in nondiabetic adults with NASH, and a randomized double blind controlled trial of metformin or vitamin E vs. placebo (TONIC) (n= 173). These studies are fully enrolled. The NAFLD database will be amended to allow further follow up of enrolled subjects, perform liver biopsies on selected subjects and add carefully defined controls as well as additional subjects with NAFLD. The rationale for this is to definitively evaluate the natural history of the disease, develop and validate biomarkers and complete ancillary studies that are still underpowered despite use of the current database, (2) to complete the numerous pilot and ancillary studies that have been initiated, (3) to perform additional therapeutic trials in adults and children with NASH. The specific studies will be based on proposals received from individual centers that are approved by the NASH CRN steering committee and the NIDDK for which funding is available, and (4) to conduct new ancillary studies proposed by individual centers. Two studies are proposed by this center: (a) to validate the metabolomic signature of NASH. Preliminary studies have identified a distinct lipidomic signature of NASH, (b) to perform a randomized controlled trial of laparoscopic adjustable band gastroplasty (LABG) for adults with NASH who have a BMI between 30-45. This trial will test the hypothesis that LABG is a safe and effective treatment of NASH. Together, all of these studies are directly aligned with the NIH liver action plan for NAFLD. Public Health Relevance: (provided by the applicant): NAFLD and NASH are important health problems and their incidence is expected to increase. During the initial funding period, the CRN has made important contributions to the field of NAFLD and NASH, however there remain numerous unanswered questions. During the next funding period, the CRN will continue to investigate risk factors, clinical aspects, natural history and optimal treatment for NASH and associated conditions